IRAK4 modulators

ABSTRACT

Compounds of Formula 0, and stereoisomers and pharmaceutically acceptable salts thereof, as well as methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of PCT/EP2018/066316, filed Jun. 19,2018 which claims the benefit of priority to International PatentApplication No. PCT/CN2017/089359, filed Jun. 21, 2017, both of whichare incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention pertains to compounds useful for inhibition ofInterleukin-1 Receptor Associated Kinase 4 (IRAK4).

BACKGROUND OF THE INVENTION

TIR-domain (Toll-Interleukin 1 Receptor-domain) containing cell surfacereceptors such as the Toll-like receptors (TLR) and the IL-1 and IL-18receptors play critical roles in innate immunity and have beenimplicated in the pathogenesis of autoimmunity. TLRs, for example,recognize pathogenic or endogenous ligands and provide a requisitesignal for dendritic cell maturation and antigen presentation to T cell.Similarly, proteins that mediate signaling from these receptors havealso been shown to play important roles in the pathogenesis ofautoimmune disorders. For example mice deficient in MyD88, an adaptorprotein that directly interacts with the TIR domain, are moresusceptible to bacterial, fungal and parasitic infections. In addition,MyD88 deficient mice are resistant to experimental autoimmuneencephalomyelitis (EAE) and streptococcal cell wall-induced arthritis.

The Interleukin-1 Receptor Associated Kinase (IRAK) family is comprisedof four family members IRAK1, IRAK2, IRAK3 (also termed IRAK-M), andIRAK4. These proteins are characterized by a typical N-terminal deathdomain that mediates interaction with MyD88-family adaptor proteins anda centrally located kinase domain. Whereas IRAK1 and IRAK4 have kinaseactivity, IRAK2 and IRAK3 are catalytically inactive. Upon activation oftheir upstream cognate receptors, IRAK4 is thought to phosphorylateIRAK1, resulting in the activation and autophosphorylation of IRAK1 andsubsequent phosphorylation of downstream substrates. Thehyperphosphorylation of IRAK1 directs its dissociation from the receptorcomplex and its eventual ubiquitylation and proteasomal degradation.Phosphorylation of downstream substrates such as Pellino-2 ultimatelyleads to the activation of the MAPKs such as p38 and c-Jun N-terminalkinase (JNK) and NF-kB followed by production of pro-inflammatorycytokines, chemokines, and destructive enzyme.

The role of IRAK4 in innate immunity and in the pathogenesis ofautoimmune diseases is emerging. See, e.g., Li et al., “IRAK-4: A novelmember of the IRAK family with the properties of an IRAK-kinase,” PNAS2002, 99(8), 5567-5572; and Flannery et al., “The interleukin-1receptor-associated kinases: Critical regulators of innate immunesignaling,” Biochem Pharm 2010, 80(12), 1981-1991. Patients withdestabilizing or null mutations in IRAK4 demonstrate defects in TLRsignaling and the production of pro-inflammatory cytokines such as IL-1and TNF as well as antiviral cytokines such as IFNα and IFNβ. Thesepatients demonstrate an increased susceptibility to gram-positivebacterial infections although they are generally resistant togram-negative bacterial, viral, and fungal infections. Similarly, IRAK4deficient mice have defects in TLR- and IL-1-mediated cytokineproduction and exhibit an increased susceptibility to infection. IRAK1deficient mice demonstrate a loss of responsiveness tolipopolysaccharides (LPS), IL-1, and IL-18 as well as impaired Th1development. These mice were resistant to experimental autoimmuneencephalomyelitis, exhibiting little or no CNS inflammation.

Accordingly, compounds that modulate the function of IRAK4 represent anattractive approach to the development of therapeutic agents for thetreatment of diseases such as inflammatory, cell proliferative andimmune-related conditions and diseases associated with IRAK-mediatedsignal transduction, such as rheumatoid arthritis, inflammatory boweldisease, multiple sclerosis, lupus, diabetes, obesity, allergic disease,psoriasis, asthma, graft rejection, cancer and sepsis.

SUMMARY OF THE INVENTION

One aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

R¹ is C₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroarylthat is optionally substituted with R^(z);

R² is halogen, oxo, CN, OH, C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkylgroup, a —(C₀₋₃alkyl)-3-11 membered heterocyclic group, —NR^(a)R^(b),—NR^(c)C(O)R^(f), —NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl),—C(O)NR^(c)R^(d), —C(O)OR^(f), —S(O)₁₋₂NR^(c)R^(d), or—(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen; oxo; CN; OR^(f);C₁₋₃haloalkoxy; —C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionallysubstituted with OH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy,or a 3-8 membered heterocyclic group,

ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-memberedsaturated or partially saturated heterocyclic group, or a 9-memberedbicyclic heteroaryl that comprises at least two heteroatoms selectedform the group consisting of N, O, and S, wherein ring A is optionallysubstituted with R^(m); provided ring A is not an optionally substituted9-membered bicyclic heteroaryl of the following formula,

R^(a), R^(b), R^(c) and R^(d) are, independently at each occurrence,hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11membered saturated heterocyclic group, a 5-6 membered monocyclicheteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or—S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8membered heterocyclic group,

-   -   wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group,        or heteroaryl ring is independently optionally substituted with        halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy,        C₁₋₃haloalkoxy, —OR^(f), —NR^(g)R^(h), or a 5-6 membered        monocyclic heteroaryl ring;

R^(e) is, independently at each occurrence, hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionallysubstituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group,wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(e), or—NR^(g)R^(h);

R^(g) and R^(h) are, independently at each occurrence, hydrogen,C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkylgroup is independently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

each R^(m) is, independently at each occurrence, halogen; oxo; CN;—OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —N^(n)R^(p); —C(O)(C₁₋₃alkyl);—(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂;C₃₋₁₀ cycloalkyl group optionally substituted with OH or halogen; a 3-11membered saturated or partially saturated heterocyclic group optionallysubstituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroarylring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy,—NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH;or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p),phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partiallysaturated heterocyclic group optionally substituted with oxo, C₁₋₃alkyl, or a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with oxo, halogen, or C₁₋₃alkyl;

R^(n), R^(p), R^(r) and R^(s) are, independently at each occurrence,hydrogen, C₁₋₆alkyl, C₃₋₆6cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11membered saturated heterocyclic group, a 5-6 membered monocyclicheteroaryl ring, —C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or—S(O)₁₋₂R^(v), or R^(r) and R^(s) are taken together to form a 5-8membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, orheteroaryl ring is independently optionally substituted with halogen,oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v),—NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring;

R^(t) and R^(u) are, independently at each occurrence, hydrogen,C₁₋₃alkyl, or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionallysubstituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(v) is, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group,wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or—NR^(t)R^(u); and

R^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(x) and R^(y) are, independently at each occurrence, C₁₋₆alkyl, orR^(x) and R^(y) are taken together to form a 6-membered heterocyclicgroup that is optionally substituted with R^(z);

each R^(z) is, independently at each occurrence, halogen; oxo; CN;—S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl);—(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂;C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11membered saturated or partially saturated heterocyclic group optionallysubstituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroarylring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy,—NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH;or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p),phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partiallysaturated heterocyclic group optionally substituted with oxo, C₁₋₃alkyl, or a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with oxo, halogen, or C₁₋₃alkyl.

Also provided is a pharmaceutical composition that comprises a compoundof the invention and a pharmaceutically acceptable carrier, diluent orexcipient.

Another aspect includes a method of preventing, treating, or lesseningthe severity of a disease or condition responsive to the inhibition ofIRAK4 in a patient, comprising administering to the patient atherapeutically effective amount of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention.

Another aspect includes a method for treating cancer in a patient,comprising administering to the patient a therapeutically effectiveamount of a compound, stereoisomer, or pharmaceutically acceptable saltof the invention.

Another aspect includes a method for treating an inflammatory orautoimmune disease in a patient, comprising administering to the patienta therapeutically effective amount of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention. In one aspect thedisease is selected from the group consisting of Crohn's disease,ulcerative colitis, inflammatory bowel disease (IBD), asthma, graftversus host disease, allograft rejection, chronic obstructive pulmonarydisease (COPD), rheumatoid arthritis, systemic lupus erythematosus,lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenileidiopathic arthritis, multiple sclerosis, neuropathic pain, gout, andgouty arthritis.

Another aspect includes a method for treating endometriosis in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound, stereoisomer, or pharmaceuticallyacceptable salt of the invention.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention in therapy, such asthe treatment of an inflammatory disease, an autoimmune disease,endometriosis, or cancer.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention in the treatment of aninflammatory disease.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention for the preparation ofa medicament for the treatment of an inflammatory disease.

Another aspect includes a compound, stereoisomer, or pharmaceuticallyacceptable salt of the invention for use in the treatment of aninflammatory disease.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention in the treatment ofcancer.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention for the preparation ofa medicament for the treatment of cancer.

Another aspect includes a compound, stereoisomer, or pharmaceuticallyacceptable salt of the invention for use in the treatment of cancer.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention in the treatment ofendometriosis.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention for the preparation ofa medicament for the treatment of endometriosis.

Another aspect includes a compound, stereoisomer, or pharmaceuticallyacceptable salt of the invention for use in the treatment ofendometriosis.

Another aspect includes a method of inhibiting IRAK4 in a cell, ex vivo,comprising contacting the cell with a compound, stereoisomer, orpharmaceutically acceptable salt of the invention.

Another aspect includes a method of inhibiting IRAK4 in a patient inneed of therapy, comprising administering to the patient a compound,stereoisomer, or pharmaceutically acceptable salt of the invention.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention to inhibit IRAK4.

Another aspect includes the use of a compound, stereoisomer, orpharmaceutically acceptable salt of the invention for the preparation ofa medicament for inhibiting IRAK4.

Another aspect includes a compound, stereoisomer, or pharmaceuticallyacceptable salt of the invention for use in inhibiting IRAK4.

Another aspect includes a kit for treating a disease or disorderresponsive to the inhibition of IRAK4. The kit can comprise a firstpharmaceutical composition comprising a compound, stereoisomer, orpharmaceutically acceptable salt of the invention, and instructions foruse.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms suchas “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted. In one example, the alkyl radical is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical isC₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, orC₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups includemethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl (—CH₂CH₂CH₂CH₂CH₂CH₂CH₃)and 1-octyl (—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃). In some embodiments,substituents for “optionally substituted alkyls” include one to fourinstances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃,C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl,isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused toone or more groups, having the number of carbon atoms designated, or ifno number is designated, up to 14 carbon atoms. One example includesaryl groups having 6-14 carbon atoms. Another example includes arylgroups having 6-10 carbon atoms. Examples of aryl groups include phenyl,naphthyl, biphenyl, phenanthrenyl, naphthacenyl,1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, andthe like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.)13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substitutedphenyl or substituted aryl means a phenyl group or aryl groupsubstituted with one, two, three, four or five substituents, forexample, 1-2, 1-3 or 1-4 substituents, such as chosen from groupsspecified herein (see “optionally substituted” definition), such as F,Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, phenyl, piperidinyl, piperizinyl,and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portionsthereof may be optionally substituted, such as by one to four instancesof substituents selected from this same list. Examples of the term“substituted phenyl” include a mono- or di(halo)phenyl group such as2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group suchas 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, aswell as trisubstituted phenyl groups where the substituents aredifferent, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonyl amino.

The terms “compound(s) of the invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of Formula 0 and the compounds of Table 1, includingstereoisomers (including atropisomers), geometric isomers, tautomers,solvates, metabolites, isotopes, salts (e.g., pharmaceuticallyacceptable salts), and prodrugs thereof. In some embodiments, solvates,metabolites, isotopes or prodrugs are excluded, or any combinationthereof.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the cycloalkyl group is 3 to 12 carbonatoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ orC₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, isC₃-C₈, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as abicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spirosystem, is C₅-C₁₂. Examples of monocyclic cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements ofbicyclic cycloalkyls having 7 to 12 ring atoms include, but are notlimited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplarybridged bicyclic cycloalkyls include, but are not limited to,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.Examples of spiro cycloalkyl include, spiro[2.2]pentane,spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane andspiro[4.5]decane. In some embodiments, substituents for “optionallysubstituted cycloalkyls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, phenyl, piperidinyl, piperizinyl, and pyrimidinyl,wherein the alkyl, aryl and heterocyclic portions thereof may beoptionally substituted, such as by one to four instances of substituentsselected from this same list.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” are used interchangeably and refer to any mono-, bi-,tricyclic or spiro, saturated, partially saturated or unsaturated,aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ringsystem, having 3 to 20 ring atoms, where the ring atoms are carbon, andat least one atom in the ring or ring system is a heteroatom selectedfrom nitrogen, sulfur or oxygen. If any ring atom of a cyclic system isa heteroatom, that system is a heterocycle, regardless of the point ofattachment of the cyclic system to the rest of the molecule. In oneexample, heterocyclyl includes 3-11 ring atoms (“members”) and includesmonocycles, bicycles, tricycles and spiro ring systems, wherein the ringatoms are carbon, where at least one atom in the ring or ring system isa heteroatom selected from nitrogen, sulfur or oxygen. In one example,heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclylincludes 1 to 3 heteroatoms. In another example, heterocyclyl includes3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selectedfrom nitrogen, sulfur or oxygen. In another example, heterocyclylincludes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatomsselected from nitrogen, sulfur or oxygen. In another example,heterocyclyl includes 3-membered monocycles. In another example,heterocyclyl includes 4-membered monocycles. In another example,heterocyclyl includes 5-6 membered monocycles, e.g., 5-6 memberedheteroaryl. In another example, heterocyclyl includes 3-11 memberedheterocycloyalkyls, such as 4-11 membered heterocycloalkyls. In someembodiments, a heterocycloalkyl includes at least one nitrogen. In oneexample, the heterocyclyl group includes 0 to 3 double bonds. Anynitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO,SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g.,[NR₄]⁺Cl⁻, [NR₄]⁺ OH⁻). Example heterocycles are oxiranyl, aziridinyl,thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl,1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl,tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl,piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclescontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocycles containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocycles contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocycle groups.Heterocycles may be optionally substituted. For example, substituentsfor “optionally substituted heterocycles” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where atleast one ring is a 5- or 6-membered aromatic ring containing from 1 to4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in anexample embodiment, at least one heteroatom is nitrogen. See, forexample, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed.Table 7-2 [1985]. Included in the definition are bicyclic groups whereany of the above heteroaryl rings are fused to an aryl ring, aheterocyclic group, or a cycloalkyl, wherein the bicyclic group isjoined to the remainder of the molecule at any position of the bicyclicgroup. In one embodiment, heteroaryl includes 5-6 membered monocyclicaromatic groups where one or more ring atoms is nitrogen, sulfur oroxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl and purinyl, aswell as benzo-fused derivatives, for example benzoxazolyl, benzofuryl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl andindolyl. Heteroaryl groups can be optionally substituted. In someembodiments, substituents for “optionally substituted heteroaryls”include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃,N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl,phenyl and heterocyclic portions thereof may be optionally substituted,such as by one to four instances of substituents selected from this samelist.

In particular embodiments, a heterocyclyl group is attached at a carbonatom of the heterocyclyl group. By way of example, carbon bondedheterocyclyl groups include bonding arrangements at position 2, 3, 4, 5,or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring,position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of apyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4,or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 ofan isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of anaziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3,4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way ofexample, nitrogen bonded heterocyclyl or heteroaryl groups includebonding arrangements at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of a isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, as defined herein.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di-and tri-fluoromethoxy and cyclopropoxy. “Haloalkoxy” refers to ahaloalkyl group, as that term is defined herein, as R.

The term “alkanoyl” refers to group (alkyl)-C(═O)—, wherein alkyl is asdefined herein. For example, C₁-C₆alkanoyl refers to a group of formula(C₁-C₅alkyl)-C(═O)—. Alkanoyl groups include, formyl, acetyl, propanoyl,isopropanoyl, butanoyl, isobutanoyl, pentanoyl, 3-methylpentanoyl, andhexanoyl.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3,4, or 5 or more, or any range derivable therein) of the substituentslisted for that group in which said substituents may be the same ordifferent. In an embodiment, an optionally substituted group has 1substituent. In another embodiment an optionally substituted group has 2substituents. In another embodiment an optionally substituted group has3 substituents. In another embodiment an optionally substituted grouphas 4 substituents. In another embodiment an optionally substitutedgroup has 5 substituents.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule. In some embodiments, an arrow together withan asterisk is used in the manner of a wavy line to indicate a point ofattachment.

In certain embodiments, divalent groups are described genericallywithout specific bonding configurations. It is understood that thegeneric description is meant to include both bonding configurations,unless specified otherwise. For example, in the group —R¹—R²—R³, if thegroup R² is described as —CH₂C(O)—, then it is understood that thisgroup can be bonded both as R¹—CH₂C(O)—R³, unless specified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, such as, for example,a human, as appropriate.

Compounds of the invention may be in the form of a salt, such as apharmaceutically acceptable salt. “Pharmaceutically acceptable salts”include both acid and base addition salts. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particular base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases include isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride,hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate,maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate,ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate,saccharinate, adipate, formate, glycolate, palmitate, L-lactate,D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate(e.g., 2-furoate or 3-furoate), napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isothionate(2-hydroxyethylsulfonate), 2-mesitylenesulphonate,2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate,L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate(2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate(camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acidsalt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate),orotate, xylate (p-xylene-2-sulphonate), and pamoic(2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all livingmicroorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include diastereomers, enantiomers,conformers and the like.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. Mixturesof diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and 1 or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or 1 meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. A “solvate” refers to anassociation or complex of one or more solvent molecules and a compoundof the present invention. Examples of solvents that form solvatesinclude water, isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, and ethanolamine. Certain compounds of the invention canexist in multiple crystalline or amorphous forms. In general, allphysical forms are intended to be within the scope of the presentinvention. The term “hydrate” refers to the complex where the solventmolecule is water.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. Such products can result,for example, from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, and imines, as well as many N-heteroatom derivatives whichcan be removed to regenerate the desired amine group. Particular aminoprotecting groups are Pmb (p-Methoxybenzyl), Boc(tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz(Carbobenzyloxy). Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups thatare stable to the conditions of subsequent reaction(s) at otherpositions of the molecule, which may be removed at the appropriate pointwithout disrupting the remainder of the molecule, to give theunprotected carboxy-group. Examples of carboxy protecting groupsinclude, ester groups and heterocyclic groups. Ester derivatives of thecarboxylic acid group may be employed to block or protect the carboxylicacid group while reactions are carried out on other functional groups onthe compound. Examples of such ester groups include substitutedarylalkyl, including substituted benzyls, such as 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, alkyl or substituted alkyl esters suchas methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl),4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl,2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esterssuch as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl,2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonyl ethyl,4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Anotherexample of carboxy-protecting groups are heterocyclic groups such as1,3-oxazolinyl. Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected carboxy”refers to a carboxy group substituted with one of the abovecarboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g., TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protecting Groups inOrganic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term“protected hydroxy” refers to a hydroxy group substituted with one ofthe above hydroxy-protecting groups.

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Mixtures of particular diastereomeric compounds may beseparated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated, or enantiomerically enriched, using the sametechniques or others known in the art. Each of the asymmetric carbon ornitrogen atoms may be in the R or S configuration and both of theseconfigurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds of the inventionincluding known amino-protecting and carboxy-protecting groups which arereleased, for example hydrolyzed, to yield the compound of the presentinvention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of apharmaceutically active substance that is less efficacious to thepatient compared to the parent drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). Prodrugs include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs oroptionally substituted phenylacetamide-containing prodrugs, and5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, forexample alkyl, alkylene or aryl, or a group having the Formula—C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same or different andare hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In aparticular embodiment, the nitrogen atom is one of the nitrogen atoms ofthe amidino group of the compounds of the invention. Prodrugs may beprepared by reacting a compound of the present invention with anactivated group, such as acyl groups, to bond, for example, a nitrogenatom in the compound to the exemplary carbonyl of the activated acylgroup. Examples of activated carbonyl compounds are those containing aleaving group bonded to the carbonyl group, and include, for example,acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acylphenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl,fluorophenoxy acyl, and difluorophenoxy acyl. The reactions aregenerally carried out in inert solvents at reduced temperatures such as−78 to about 50° C. The reactions may also be carried out in thepresence of an inorganic base, for example potassium carbonate or sodiumbicarbonate, or an organic base such as an amine, including pyridine,trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of the inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁-C₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. Mammals include, but are notlimited to, farm animals (such as cows), sport animals, pets (such asguinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.In certain embodiments, a mammal is a human. In embodiments comprisingadministration of a compound of to a patient, the patient is typicallyin need thereof.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., IRAK4 activity)compared to normal.

In some embodiments, a compound of Formula 0, such as a compound ofTable 1, is selective for inhibition of IRAK4 over IRAK1. By “selectivefor inhibition” it is meant that the compound is at least a 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 99%, or more, or any range derivable therein, betterinhibitor of IRAK4 activity compared to IRAK1 activity, or is at least a2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better inhibitorof IRAK4 activity compared to IRAK1 activity.

A “therapeutically effective amount” means an amount of a compound ofthe present invention, such as a compound of Formula 0, that (i) treatsor prevents the particular disease, condition or disorder, or (ii)attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, and optionally (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition or disorder described herein. In some embodiments,the therapeutically effective amount is an amount sufficient to decreaseor alleviate the symptoms of an autoimmune or inflammatory disease(e.g., lupus). In some embodiments, a therapeutically effective amountis an amount of a chemical entity described herein sufficient tosignificantly decrease the activity or number of B-cells. In the case ofcancer, the therapeutically effective amount of the drug may reduce thenumber of cancer cells; reduce the tumor size; inhibit (i.e., slow tosome extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth or kill existingcancer cells, it may be cytostatic or cytotoxic. For cancer therapy,efficacy can, for example, be measured by assessing the time to diseaseprogression (TTP) or determining the response rate (RR).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, compounds of the invention,are used to delay development of a disease or disorder or to slow theprogression of a disease or disorder. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome inwhich an excessive or unregulated inflammatory response leads toexcessive inflammatory symptoms, host tissue damage, or loss of tissuefunction. “Inflammatory disorder” also refers to a pathological statemediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute, orwall off (sequester) both the injurious agent and the injured tissue.Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with a compound of thepresent invention, such as a compound of Formula 0, encompass disordersassociated with reactions of the specific defense system as well as withreactions of the nonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity responses mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” refers to inflammatory disordersthat are mediated by leukocytes that are incapable of immunologicalmemory (e.g., granulocytes, and macrophages). Examples of inflammationthat result, at least in part, from a reaction of the nonspecificdefense system include inflammation associated with conditions such asadult (acute) respiratory distress syndrome (ARDS) or multiple organinjury syndromes; reperfusion injury; acute glomerulonephritis; reactivearthritis; dermatoses with acute inflammatory components; acute purulentmeningitis or other central nervous system inflammatory disorders suchas stroke; thermal injury; inflammatory bowel disease; granulocytetransfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissueinjury is associated with humoral or cell-mediated responses to thebody's own constituents. Non-limiting examples of autoimmune diseasesinclude rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treatedaccording to the methods of this invention include, but are not limitedto, asthma, rhinitis (e.g., allergic rhinitis), allergic airwaysyndrome, atopic dermatitis, bronchitis, rheumatoid arthritis,psoriasis, lupus, chronic obstructive pulmonary disease (COPD), contactdermatitis, chronic obstructive pulmonary disease and delayedhypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and relatedterms refer to or describe the physiological condition in mammals thatis typically characterized by unregulated cell growth. A “tumor”comprises one or more cancerous cells. Examples of cancer includecarcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma,leukemia, and myeloid or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer) and lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung. Other cancers include skin, keratoacanthoma,follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,hepatocellular, gastric, stomach, gastrointestinal, small intestine,large intestine, pancreatic, cervical, ovarian, liver, bladder,hepatoma, breast, colon, rectal, colorectal, genitourinary, biliarypassage, thyroid, papillary, hepatic, endometrial, uterine, salivarygland, kidney or renal, prostate, testis, vulval, peritoneum, anal,penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Celllymphoma (DLBCL), central nervous system, brain, head and neck,Hodgkin's, and associated metastases. Examples of neoplastic disordersinclude myeloproliferative disorders, such as polycythemia vera,essential thrombocytosis, myelofibrosis, such as primary myelofibrosis,and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents are well-known in the art and includeexamples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. Additionally, chemotherapeutic agentsinclude pharmaceutically acceptable salts, acids or derivatives of anyof chemotherapeutic agents, as well as combinations of two or more ofthem.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the invention, include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically-labeledcompounds (e.g., those labeled with ³H and ¹⁴C) can be useful incompound or substrate tissue distribution assays. Tritiated (i.e., ³H)and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements). In some embodiments,in compounds of the invention, one or more carbon atoms are replaced by¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by following procedures analogous tothose disclosed in the Schemes or in the Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention. Furthermore, any compound or composition ofthe invention may be used in any method of the invention, and any methodof the invention may be used to produce or to utilize any compound orcomposition of the invention.

If any discrepancy exists between a structure and its name, thestructure prevails.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternative are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

IRAK4 Inhibitors

One aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

R¹ is C₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroarylthat is optionally substituted with R^(z);

R² is halogen, oxo, CN, OH, C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkylgroup, a —(C₀₋₃alkyl)-3-11 membered heterocyclic group, —NR^(a)R^(b),—NR^(e)C(O)R^(f), —NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl),—C(O)NR^(c)R^(d), —C(O)OR^(f), —S(O)₁₋₂NR^(c)R^(d), or—(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen; oxo; CN; OR^(f);C₁₋₃haloalkoxy; —C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionallysubstituted with OH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy,or a 3-8 membered heterocyclic group,

ring A is a 5-membered heteroaryl, a 6-membered heteroaryl, a 6-memberedsaturated or partially saturated heterocyclic group, or a 9-memberedbicyclic heteroaryl that comprises at least two heteroatoms selectedform the group consisting of N, O, and S, wherein ring A is optionallysubstituted with R^(m); provided ring A is not an optionally substituted9-membered bicyclic heteroaryl of the following formula,

R^(a), R^(b), R^(c) and R^(d) are, independently at each occurrence,hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11membered saturated heterocyclic group, a 5-6 membered monocyclicheteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or—S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, orheteroaryl ring is independently optionally substituted with halogen,oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(f),—NR^(g)R^(h), or a 5-6 membered monocyclic heteroaryl ring;

R^(e) is, independently at each occurrence, hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionallysubstituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group,wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, —OR^(c), or—NR^(g)R^(h);

R^(g) and R^(h) are, independently at each occurrence, hydrogen,C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl or cycloalkylgroup is independently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

each R^(m) is, independently at each occurrence, halogen; oxo; CN;—OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl);—(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂;C₃₋₁₀ cycloalkyl group optionally substituted with OH or halogen; a 3-11membered saturated or partially saturated heterocyclic group optionallysubstituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroarylring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy,—NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH;or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p),phenyl, C₃₋₁₀ocycloalkyl, a 3-11 membered saturated or partiallysaturated heterocyclic group optionally substituted with oxo, C₁₋₃alkyl, or a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with oxo, halogen, or C₁₋₃alkyl;

R^(n)R^(p), R^(r) and R^(s) are, independently at each occurrence,hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11membered saturated heterocyclic group, a 5-6 membered monocyclicheteroaryl ring, —C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or—S(O)₁₋₂R^(v), or R^(r) and R^(s) are taken together to form a 5-8membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, orheteroaryl ring is independently optionally substituted with halogen,oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v),—NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring;

R^(t) and R^(u) are, independently at each occurrence, hydrogen,C₁₋₃alkyl, or C₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionallysubstituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(v) is, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group,wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or—NR^(t)R^(u); and

R^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionallysubstituted with halogen, oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, or C₁₋₃haloalkoxy;

R^(x) and R^(y) are, independently at each occurrence, C₁₋₆alkyl, orR^(x) and R^(y) are taken together to form a 6-membered heterocyclicgroup that is optionally substituted with R^(z);

each R^(z) is, independently at each occurrence, halogen; oxo; CN;—S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl);—(C₀₋₃alkyl)C(O)NR^(f)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂;C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11membered saturated or partially saturated heterocyclic group optionallysubstituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroarylring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy,—NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH;or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p),phenyl, C₃₋₁₀ocycloalkyl, a 3-11 membered saturated or partiallysaturated heterocyclic group optionally substituted with oxo, C₁₋₃alkyl, or a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with oxo, halogen, or C₁₋₃alkyl.

In some embodiments, R¹ is —NR^(x)R^(y).

In some embodiments, R^(x) and R^(y) are taken together to form a6-membered heterocyclic group that is optionally substituted with R^(z).

In some embodiments, R^(x) and R^(y) are taken together to form amorpholino group that is optionally substituted with R^(z).

In some embodiments, R¹ is a 6-membered heteroaryl that is optionallysubstituted with R^(z).

In some embodiments, R¹ is pyridyl that is optionally substituted withR^(z).

In some embodiments, R¹ is selected from the group consisting of

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, ring A is selected from the group consisting of

In some embodiments, ring A is selected from the group consisting of

In some embodiments, R^(m) is selected from the group consisting ofchloro, oxo, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, CN,methoxy, OH, isopropoxy, 2,2,2-trifluoroethyl, 1-hydroxyethyl,1-methoxyethyl, 2-hydroxyprop-2-yl, morpholino, 20methylmorpholino, and1H-pyrrol-3-yloxy.

In some embodiments, R^(m) is 3-methylmorpholino.

In some embodiments, the compound, stereoisomer, or pharmaceuticallyacceptable salt is selected from the group consisting of

and stereoisomers and pharmaceutically acceptable salts thereof.

In some embodiments, the compound, stereoisomer, or pharmaceuticallyacceptable salt is selected from the compounds shown in Table 1 below,and from stereoisomers and pharmaceutically acceptable salts thereof.

TABLE 1 Exemplary compounds of the present invention. Salts of suchcompounds are also contemplated. See the Examples section forpreparation of such compounds. # Structure Name 1

N-[6-morpholino-1-oxo-2-[rac-(2R)- 2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]imidazo[1,2- b]pyridazine-3-carboxamide 2

2-methyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl] oxazole-4-carboxamide 3

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]-2- oxo-1H-pyridine-3-carboxamide 4

1-methyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]-2- oxo-pyridine-3-carboxamide 5

1-ethyl-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]-2- oxo-pyridine-3-carboxamide 6

1-isopropyl-N-[6-morpholino-l- oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin- 5-yl]-2-oxo-pyridine-3- carboxamide 7

1-cyclopropyl-N-[6-morpholino- 1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]-2-oxo-pyridine- 3-carboxamide 8

6-cyano-N-[6-morpholino-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl] pyridine-2-carboxamide 9

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 2-(4-pyridyl)oxazole-4- carboxamide 10

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 2-[rac-(3S)-3-methylmorpholin-4-yl]oxazole-4-carboxamide 11

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-isopropoxy-pyridine-2- carboxamide 12

4-hydroxy-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]pyridine-2- carboxamide 13

N-[6-(dimethylamino)-1-oxo-2- [rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-pyrrolidin-3-yloxy-pyridine-2-carboxamide 14

2-methyl-N-[6-(5-methyl-2- pyridyl)-1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl- butyl]isoindolin-5-yl]oxazole- 5-carboxamide15

2-morpholino-N-[6-morpholino- 1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]oxazole-4- carboxamide 16

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 2-[rac-(3R)-3-methylmorpholin-4-yl]oxazole-4-carboxamide 17

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-(trifluoromethyl)pyridine-2-carboxamide 18

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5- yl]-6-(trifluoromethyl)pyridine-2-carboxamide 19

N-[6-(dimethylamino)-1-oxo- 2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-methoxy-pyridine-2- carboxamide 20

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl] thieno[2,3-b]pyrazine-7- carboxamide 21

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-[rac-(1R)-1-hydroxyethyl]pyridine-2-carboxamide 22

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-[rac-(1S)-1-hydroxyethyl]pyridine-2-carboxamide 23

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-[rac-(1R)-1-methoxyethyl]pyridine-2-carboxamide 24

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-[rac-(1S)-1-methoxyethyl]pyridine-2-carboxamide 25

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 6-(2,2,2-trifluoroethyl)pyridine-2-carboxamide 26

5-methyl-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxamide 27

6-(1-hydroxy-1-methyl-ethyl)- N-[6-morpholino-1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3- methyl-butyl]isoindolin-5-yl]pyridine-2-carboxamide 28

N-[6-isopropoxy-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 7-methyl-imidazo[1,2-b]pyridazine-3-carboxamide 29

7-methyl-N-[6-morpholino-1- oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]imidazo[1,2-b]pyridazine-3-carboxamide 30

N-[6-[4-(oxetan-3-yl)piperazin- 1-yl]-1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]thieno[2,3-b]pyrazine-7-carboxamide 31

N-[6-[4-(oxetan-3-yl)piperazin- 1-yl]-1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl-butyl] isoindolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide 32

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- 1H-benzimidazole-4- carboxamide 33

5-chloro-1-methyl-N-[6- morpholino-1-oxo-2-[rac-(2R)-2-fluoro-3-hydroxy-3-methyl- butyl]isoindolin-5-yl]pyrazole-4-carboxamide 34

N-[6-morpholino-1-oxo-2-[rac- (2R)-2-fluoro-3-hydroxy-3-methyl-butyl]isoindolin-5-yl]- [1,2,4]triazolo[1,5-a]pyridine-5-carboxamide

Synthesis of IRAK4 Inhibitors

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below. The starting materials and reagents used in preparingthese compounds generally are either available from commercialsuppliers, such as Aldrich Chemical Co., or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis;Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive OrganicTransformations, 2nd edition Wiley-VCH, New York 1999; ComprehensiveOrganic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon,Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky andC. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; ComprehensiveHeterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds)Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons:New York, 1991, vol. 1-40. The following synthetic reaction schemes aremerely illustrative of some methods by which the compounds of thepresent invention can be synthesized, and various modifications to thesesynthetic reaction schemes can be made and will be suggested to oneskilled in the art having referred to the disclosure contained in thisApplication.

For illustrative purposes, reaction Schemes below provide routes forsynthesizing the compounds of the invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used. Although somespecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can besubstituted to provide a variety of derivatives or reaction conditions.In addition, many of the compounds prepared by the methods describedbelow can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature, or,about 20° C.

Some compounds in following schemes are depicted with generalizedsubstituents; however, one skilled in the art will immediatelyappreciate that the nature of the R groups can varied to afford thevarious compounds contemplated in this invention. Moreover, the reactionconditions are exemplary and alternative conditions are well known. Thereaction sequences in the following examples are not meant to limit thescope of the invention as set forth in the claims.

Methods of Treatment with and Uses of IRAK 4 Inhibitors

Compounds of the present invention are useful as IRAK4 inhibitors.Accordingly, in one embodiment is provided a method of contacting acell, such as an ex vivo cell, with a compound of the present inventionto inhibit IRAK4 activity in the cell.

Also provided is a pharmaceutical composition comprising a compound ofFormula 0, or a stereoisomer or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient, carrier ordiluent. Compounds of the invention, including pharmaceuticalcompositions comprising such compounds, may be used in the methodsdescribed herein.

Further provided is a method of preventing, treating, or lessening theseverity of a disease or condition responsive to the inhibition of IRAK4in a patient, comprising administering to the patient a therapeuticallyeffective amount of a compound of the present invention, or astereoisomer or pharmaceutically acceptable salt thereof.

Also provided is a method for treating cancer in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of the present invention, or a stereoisomer or pharmaceuticallyacceptable salt thereof.

Further provided is a method for treating an inflammatory or autoimmunedisease in a patient, comprising administering to the patient atherapeutically effective amount of a compound of the present invention,or a stereoisomer or pharmaceutically acceptable salt thereof. In someembodiments, the disease is selected from the group consisting ofCrohn's disease, ulcerative colitis, inflammatory bowel disease (IBD),asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, systemiclupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis,systemic onset juvenile idiopathic arthritis, multiple sclerosis,neuropathic pain, gout, and gouty arthritis.

In some embodiments, other diseases and conditions responsive to theinhibition of IRAK4 that can be treated using a compound of the presentinvention include metabolic syndromes, atherosclerosis, andneurodegeneration.

Further provided is the use of a compound of the present invention, or astereoisomer or pharmaceutically acceptable salt thereof, in therapy. Insome embodiments, use of a compound of the present invention, or astereoisomer or pharmaceutically acceptable salt thereof, is provided inthe treatment of an inflammatory disease. In some embodiments, use of acompound of the present invention, or a stereoisomer or pharmaceuticallyacceptable salt thereof, is provided for the preparation of a medicamentfor the treatment of an inflammatory disease. Furthermore, in someembodiments, a compound of the present invention, or a stereoisomer orpharmaceutically acceptable salt thereof, is provided for use in thetreatment of an inflammatory disease.

In some embodiments, a disease or condition that may be treated isselected from the group consisting of acute kidney injury, acuterespiratory distress syndrome, acute lung injury, adult onset Still'sdisease, allergic airway syndrome, allergic rhinitis, allograftrejection, asthma, atherosclerosis, atopic dermatitis, bronchitis,calcium pyrophosphate deposition disease (CPPD) also known as pseudogout, cerebrovascular accident (e.g., stroke), chronic kidney disease,chronic obstructive pulmonary disease (COPD), contact dermatitis,Crohn's disease, cryopyrin-associated periodic syndromes (CAPS),cutaneous lupus, delayed hypersensitivity, diabetes, endometriosis,gout, gouty arthritis, graft vs host disease, graft rejection,inflammatory bowel disease (IBD), inflammatory myositis (e.g.,polymyositis, dermatomyositis), interstitial lung disease, lupus, lupusnephritis, metabolic syndrome, multiple sclerosis, neurodegeneration,neuropathic pain, non-alcoholic fatty liver disease, obesity, psoriasis,rheumatoid arthritis, rhinitis, scleroderma, sepsis, Sjogren's syndrome,systemic lupus erythematosus, systemic onset juvenile idiopathicarthritis, systemic sclerosis and ulcerative colitis.

Also provided is a method of inhibiting IRAK4 in a patient in need oftherapy, comprising administering to the patient a compound of thepresent invention.

Dosage & Administration

The present invention provides pharmaceutical compositions ormedicaments containing the compounds of the invention and at least onetherapeutically inert carrier, diluent or excipient, as well as methodsof using the compounds of the invention to prepare such compositions andmedicaments. In one example, compounds of Formula 0, or a stereoisomeror pharmaceutically acceptable salt thereof, with the desired degree ofpurity may be formulated by mixing with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a dosage form at ambient temperatureand at the appropriate pH. The pH of the formulation depends mainly onthe particular use and the concentration of compound, but typicallyranges anywhere from about 3 to about 8. In one example, a compound ofFormula 0 is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of Formula 0 are sterile. The compound may bestored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the severity ofthe disorder, the particular patient being treated, the clinicalcondition of the individual patient, the cause of the disorder, the siteof delivery of the agent, the method of administration, the schedulingof administration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governedby such considerations, and is the minimum amount necessary to inhibitIRAK4 activity. Typically such amount may be below the amount that istoxic to normal cells, or the patient as a whole.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing a compound of Formula 0, or astereoisomer or pharmaceutically acceptable salt thereof, which matricesare in the form of shaped articles, e.g. films, or microcapsules.Examples of sustained-release matrices include polyesters, hydrogels(for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers such as the LUPRON DEPOT™ (injectable microspherescomposed of lactic acid-glycolic acid copolymer and leuprolide acetate),and poly-D-(−)-3-hydroxybutyric acid.

A dose to treat human patients may range from about 0.1 mg to about 1000mg of a compound of Formula 0, or a stereoisomer or pharmaceuticallyacceptable salt thereof. A typical dose may be about 1 mg to about 300mg of the compound. A dose may be administered once a day (QD), twiceper day (BID), or more frequently, depending on the pharmacokinetic andpharmacodynamic properties, including absorption, distribution,metabolism, and excretion of the particular compound. In addition,toxicity factors may influence the dosage and administration regimen.When administered orally, the pill, capsule, or tablet may be ingesteddaily or less frequently for a specified period of time. The regimen maybe repeated for a number of cycles of therapy.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal, epidural and intranasal, and,if desired for local treatment, intralesional administration. Parenteralinfusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, H. C., et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,R. C., Handbook of Pharmaceutical Excipients, Chicago, PharmaceuticalPress, 2005. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

For oral administration, tablets containing various excipients, such ascitric acid may be employed together with various disintegrants such asstarch, alginic acid and certain complex silicates and with bindingagents such as sucrose, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften useful for tableting purposes. Solid compositions of a similartype may also be employed in soft and hard filled gelatin capsules.Preferred materials, therefore, include lactose or milk sugar and highmolecular weight polyethylene glycols. When aqueous suspensions orelixirs are desired for oral administration the active compound thereinmay be combined with various sweetening or flavoring agents, coloringmatters or dyes and, if desired, emulsifying agents or suspendingagents, together with diluents such as water, ethanol, propylene glycol,glycerin, or combinations thereof.

An example of a suitable oral dosage form is a tablet containing about25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the inventioncompounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodiumcroscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about1-10 mg magnesium stearate. The powdered ingredients are first mixedtogether and then mixed with a solution of the PVP. The resultingcomposition can be dried, granulated, mixed with the magnesium stearateand compressed to tablet form using conventional equipment. An exampleof an aerosol formulation can be prepared by dissolving the compound,for example 5-400 mg, of the invention in a suitable buffer solution,e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodiumchloride, if desired. The solution may be filtered, e.g., using a 0.2micron filter, to remove impurities and contaminants.

In one embodiment, the pharmaceutical composition also includes at leastone additional anti-proliferative agent.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of Formula 0, or a stereoisomer orpharmaceutically acceptable salt thereof. A further embodiment includesa pharmaceutical composition comprising a compound of Formula 0, or astereoisomer or pharmaceutically acceptable salt thereof, together witha pharmaceutically acceptable carrier or excipient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula 0 may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein. The second compound of the pharmaceutical combinationformulation or dosing regimen preferably has complementary activities tothe compound of Formula 0 such that they do not adversely affect eachother. The combination therapy may provide “synergy” and prove“synergistic”, i.e., the effect achieved when the active ingredientsused together is greater than the sum of the effects that results fromusing the compounds separately.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes co-administration, using separate formulationsor a single pharmaceutical formulation, and consecutive administrationin either order, wherein preferably there is a time period while both(or all) active agents simultaneously exert their biological activities.

Combination therapies according to the present invention thus comprisethe administration of at least one compound of Formula 0, or astereoisomer or pharmaceutically acceptable salt thereof, and the use ofat least one other treatment method. The amounts of the compound(s) ofFormula 0 and the other pharmaceutically active agent(s) and therelative timings of administration will be selected in order to achievethe desired combined therapeutic effect.

In some embodiments, a second agent that may be employed in combinationtherapy with a compound described herein may be an inhibitor of Bruton'styrosine kinase (BTK), such as a small molecule BTK inhibitor. In someembodiments, the second agent may be prednisone.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula 0, or astereoisomer or pharmaceutically acceptable salt thereof. The kit mayfurther comprise a label or package insert on or associated with thecontainer. The term “package insert” is used to refer to instructionscustomarily included in commercial packages of therapeutic products,that contain information about the indications, usage, dosage,administration, contraindications and/or warnings concerning the use ofsuch therapeutic products. Suitable containers include, for example,bottles, vials, syringes, blister pack, etc. The container may be formedfrom a variety of materials such as glass or plastic. The container mayhold a compound of Formula 0 or a formulation thereof which is effectivefor treating the condition and may have a sterile access port (forexample, the container may be an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). At leastone active agent in the composition is a compound of Formula 0.Alternatively, or additionally, the article of manufacture may furthercomprise a second container comprising a pharmaceutical diluent, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula 0, such as tablets or capsules. Sucha kit can include a number of unit dosages. An example of such a kit isa “blister pack”. Blister packs are well known in the packaging industryand are widely used for packaging pharmaceutical unit dosage forms.

EXAMPLES

The following examples illustrate the preparation and biologicalevaluation of compounds within the scope of the invention. Theseexamples and preparations which follow are provided to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation of intermediate(R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one

a.6-Chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one

To a stirred solution of methyl2-(bromomethyl)-5-chloro-4-nitro-benzoate (WO2013/079505, 4.5 g, 14.6mmol) in methanol (90 mL) was added trimethylamine (2.95 g, 29.2 mmol)and (3R)-4-amino-3-fluoro-2-methyl-butan-2-ol (WO2014/074675, 3.5 g,29.2 mmol). The mixture was stirred at 70° C. for 2 h under nitrogen.The reaction mixture was concentrated and purified by flashchromatography (40-63% ethyl acetate in petroleum ether) to afford6-chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one(quant. yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s,1H), 8.03; (s, 1H), 4.91; (d, J=2.6 Hz, 1H), 4.75-4.58; (m, 2H), 4.47;(ddd, J=49.2, 9.4, 1.9 Hz, 1H), 4.00; (ddd, J=38.6, 14.9, 1.9 Hz, 1H),3.74; (ddd, J=16.2, 14.9, 9.4 Hz, 1H), 3.34-3.23; (m, 1H), 1.18; (dd,J=4.9, 1.7 Hz, 6H). LCMS (ESI): m/z=317.1; [M+H]⁺.

b.2-[(2R)-2-Fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one

To a solution of6-chloro-2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-5-nitro-isoindolin-1-one(1.3 g, 4.1 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.2 mmol) indimethyl sulfoxide (20 mL) was added morpholine (715 mg, 8.21 mmol). Thereaction mixture was stirred at 70° C. for 16 h. The reaction mixturewas diluted with water (50 mL) and extracted with ethyl acetate (100mL×3). The organics were washed with brine (100 mL×2), dried over sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (eluting gradient: 0-60% ethyl acetate in petroleumether) to afford2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one(1.3 g, 86% yield) as a yellow solid. LCMS (ESI): m/z=368.2; [M+H]⁺.

c.(R)-5-Amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one

To a stirred solution of2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-5-nitro-isoindolin-1-one(1.66 g, 4.52 mmol) in ethanol (30 mL) and water (6 mL) was added iron(1.26 g, 23 mmol) and ammonium chloride (1.21 g, 23 mmol). The mixturewas stirred at 80° C. for 2 h under nitrogen, after which it wasfiltered and concentrated. The crude product was purified bychromatography on silica gel (eluting gradient: 0-5% methanol indichloromethane) to give(R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one(1.23 g, 81% yield) as an orange solid. LCMS (ESI): m/z=338.0; [M+H]⁺.

Example 1(R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

A flask equipped with a stir bar under a nitrogen atmosphere was chargedwith imidazo[1,2-b]pyridazine-3-carboxylic acid (27 mg, 0.16 mmol).N,N-Dimethylformamide (1.0 mL) was added and the mixture was cooled 0°C. (7-Azabenzotriazol-1-yloxy)tripyrrolidino-phosphoniumhexafluorophosphate (89 mg, 0.16 mmol) was added followed by2,4,6-trimethylpyridine (0.022 mL, 0.16 mmol).(R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one(50 mg, 0.15 mmol) was added, and the ice bath was removed allowing thereaction to stir at room temperature for 3 h. The reaction mixture wasconcentrated and the residue was purified by preparative HPLC (XbridgePrep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B:10 mM ammonium bicarbonate in water) to afford(R)—N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide(9.3 mg, 13%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.41; (s,1H), 9.01; (dd, J=4.6, 1.5 Hz, 1H), 8.76; (s, 1H), 8.52; (s, 1H), 8.45;(dd, J=9.2, 1.5 Hz, 1H), 7.61; (s, 1H), 7.58; (dd, J=9.3, 4.6 Hz, 1H),4.90; (s, 1H), 4.60-4.47; (m, 2H), 4.39; (dd, J=9.3, 1.8 Hz, 1H), 4.00;(dd, J=14.9, 1.6 Hz, 1H), 3.90-3.83; (m, 4H), 3.78-3.63; (m, 1H),3.00-2.89; (m, 4H), 1.24-1.13; (s, 6H). MS (ESI): m/z=483.2; [M+1]⁺.

Example 2.(R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-2-methyloxazole-4-carboxamide

To a solution of(R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one(100 mg, 0.30 mmol),1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (225 mg, 0.59 mmol),N,N-diisopropylethylamine (0.34 mL, 2.1 mmol) in N,N-dimethylformamide(3 mL) was added 2-methyl-1,3-oxazole-4-carboxylic acid (56 mg, 0.44mmol). The mixture was stirred at 30° C. for 12 h and filtered. Thefiltrate was concentrated and purified by reverse phase chromatography(Xtimate C18 150*25 mm*5 um, water (0.05% ammonia hydroxidev/v)-acetonitrile) to afford(R)—N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-2-methyloxazole-4-carboxamide(30 mg, 23%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.28; (s,1H), 8.66; (s, 1H), 8.21; (s, 1H), 7.66; (s, 1H), 4.63-4.43; (m, 3H),4.28-4.14; (m, 1H), 4.00 (t, J=4.4 Hz, 4H), 3.72-3.63; (m, 1H), 2.96;(t, J=4.0 Hz, 4H), 2.55; (s, 3H), 1.34; (s, 3H), 1.31; (s, 3H). LCMS(ESI): m/z=447.2; [M+H]⁺.

The following compounds were prepared using a procedure similar to thatdescribed in Example 2.

Ex. Name Structure NMR, MS 3 (R)-N-(2-(2- Fluoro-3- hydroxy-3-methylbutyl)- 6-morpholino- 1-oxoisoindolin- 5-yl)-2-oxo-1,2-dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, DMSO- d₆) δ 12.83 (d, J = 6 Hz, 1H), 12.68 (s, 1H),8.78 (s, 1H), 8.50 (dd, J = 7.2, 2.0 Hz, 1H), 7.84-7.81 (m, 1H), 7.49(s, 1H), 6.57 (t, J = 7.2 Hz, 1H), 4.57-4.46 (m, 3H), 3.96-3.70 (m, 5H),3.68-3.64 (m, 1H), 2.88-2.86 (m, 4H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS(ESI): m/z = 459.2 [M + H]⁺. 4 (R)-N-(2-(2- Fluoro-3- hydroxy-3-methylbutyl)- 6-morpholino- 1-oxoisoindolin- 5-yl)-1-methyl- 2-oxo-1,2-dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.74 (s, 1H), 8.83 (s, 1H), 8.62 (d, J = 7.6,2.0 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J = 6.4, 2.0 Hz, 1H), 6.48-6.45 (m,1H), 4.61-4.42 (m, 3H), 4.26- 4.13 (m, 1H), 4.06-4.05 (m, 4H), 3.72 (s,3H), 3.69-3.55 (m, 1H), 2.97 (t, J = 4.4 Hz, 4H), 1.34 (s, 3H), 1.29 (s,3H). LCMS (ESI): m/z = 473.2 [M + H]⁺. 5 (R)-1-Ethyl-N- (2-(2-fluoro-3-hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin-5- yl)-2-oxo-1,2-dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.77 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.01(d, J = 4.4 Hz, 1H), 7.66 (s, 1H), 6.59 (t, J = 7.2 Hz, 1H), 4.66-4.54(m, 3H), 4.25-4.19 (m, 3H), 4.04 (m, 4H), 3.77-3.75 (m, 1H), 2.98-2.96(m, 4H), 1.44 (t, J = 6.8 Hz, 3H), 1.30 (s, 6H). LCMS (ESI): m/z = 487.2[M + H]⁺. 6 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin- 5-yl)-1- isopropyl-2- oxo-1,2-dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.05(dd, J = 6.4, 1.6 Hz, 1H), 7.64 (s, 1H), 6.63 (t, J = 7.2 Hz, 1H), 5.41-5.38 (m, 1H), 4.87-4.44 (m, 3H), 4.14-4.03 (m, 5H), 3.76- 3.70 (m, 1H),2.97-2.95 (m, 4H), 1.48 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). LCMS (ESI):m/z = 501.3 [M + H]⁺. 7 (R)-1-Cyclopropyl- N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)-6- morpholino-1- oxoisoindolin-5- yl)-2-oxo-1,2-dihydropyridine- 3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.74 (s, 1H), 8.53 (dd, J = 7.2, 2.0 Hz, 1H),7.94 (dd, J = 6.8, 2.0 Hz, 1H), 7.65 (s, 1H), 6.55 (t, J = 7.2 Hz, 1H),4.65-4.53 (m, 3H), 4.09-4.05 (m, 5H), 3.77-3.70 (m, 1H), 3.54-3.53 (m,1H), 2.98-2.96 (m, 4H), 1.30 (s, 6H), 1.24- 1.20 (m, 2H), 1.02-1.00 (m,2H). LCMS (ESI): m z = 499.3 [M + H]⁺. 8 (R)-6-Cyano-N- (2-(2-fluoro-3-hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)picolinamide

¹H NMR (400 MHz, CDCl₃) δ 11.36 (s, 1H), 8.76 (s, 1H), 8.55 (d, J = 7.2Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.74 (s,1H), 4.67-4.46 (m, 3H), 4.29-4.14 (m, 1H), 4.06 (t, J = 4.4 Hz, 4H),3.73-3.66 (m, 1H), 3.00 (t, J = 4.4 Hz, 4H), 2.41 (s, 1H), 1.35 (s, 3H),1.33 (s, 3H). LCMS (ESI): m/z = 468.1 [M + H]⁺. 9 (R)-N-(2-(2- Fluoro-3-hydroxy-3- methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-2-(pyridin-4-yl) oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.86 (d, J = 4.8 Hz, 2H), 8.72(s, 1H), 8.46 (s, 1H), 7.94 (d, J = 4.8 Hz, 2H), 7.73 (s, 1H), 4.66-4.46 (m, 3H), 4.27-4.14 (m, 1H), 4.07 (br s, 4H), 3.69- 3.65 (m, 1H),3.02 (br s, 4H), 2.36 (s, 1H), 1.34 (s, 3H), 1.33 (s, 3H). LCMS (ESI):m/z = 510.2 [M+H]+. 10 N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]-6-morpholino- 1-oxo- isoindolin-5- yl]-2-[(3S)-3- methylmorpholin-4-yl]oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.71 (s, 1H), 7.89 (s, 1H),7.67 (s, 1H), 4.63-4.44 (m, 3H), 4.21-4.04 (m, 3H), 3.98-3.95 (m, 4H),3.80-3.77 (m, 2H), 3.72-3.63 (m, 3H), 3.52-3.44 (m, 1H), 2.96 (br s,4H), 2.32 (s, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (s, 3H), 1.32 (s, 3H).LCMS (ESI): mz = 532.2 [M + H]⁺. 11 N-[6- (Dimethylamino)-2-[(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5-yl]-6-isopropoxy- pyridine-2- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.24 (s, 1H), 8.79 (s, 1H), 7.88-7.73 (m,3H), 6.91 (d, J = 8.0 Hz, 1H), 5.48-5.42 (m, 1H), 4.64-4.45 (m, 3H),4.25-4.13 (m, 1H), 3.72-3.66 (m, 1H), 2.76 (s, 6H), 2.49 (br s, 1H),1.47 (d, J = 5.2 Hz, 6H), 1.34 (s, 3H), 1.32 (3H each). LCMS (ESI): m/z= 459.2 [M + H]⁺. 12 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin- 5-yl)-4- hydroxypico- linamide

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 8.67 (s, 1H), 8.46 (d, J =4.4 Hz, 1H), 7.57-7.54 (m, 2H), 7.01 (s, 1H), 4.93 (s, 1H), 4.60-4.37(m, 3H), 3.99-3.89 (m, 5H), 3.71- 3.69 (m, 1H), 2.92 (t, J = 4.4 Hz,4H), 1.18 (s, 6H). LCMS (ESI): m z = 459.2 [M + H]⁺. 13 N-[6-(Dimethylamino)- 2-[(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1-oxo-isoindolin- 5-yl]-6- pyrrolidin-3- yloxy-pyridine- 2-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.96 (s, 1H), 8.77 (s, 1H), 8.00 (d, J = 7.6Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (d, J = 8.4 Hz,1H), 5.80-5.75 (m, 1H), 4.64-4.44 (m, 3H), 4.22-4.14 (m, 1H), 3.77-3.60(m, 5H), 2.76 (s, 6H), 2.54-2.46 (m, 2H), 1.34 (s, 3H), 1.32 (s, 3H).LCMS (ESI): m/z = 486.3 [M + H]⁺. 14 (R)-N-(2-(2- Fluoro-3- hydroxy-3-methylbutyl)- 6-(5-methyl- pyridin-2-yl)- 1-oxoisoindolin- 5-yl)-2-methyloxazole- 5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 14.07 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H),8.23 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.71(s, 1H), 4.73-4.49 (m, 3H), 4.29-4.16 (m, 1H), 3.72-3.66 (m, 1H), 2.65(s, 3H), 2.47 (s, 3H), 2.34 (s, 1H), 1.36 (s, 3H), 1.34 (s, 3 H). LCMS(ESI): m/z = 453.1 [M + H]⁺. 15 (R)-N-(2-(2- Fluoro-3- hydroxy-3-methylbutyl)-6- morpholino-1- oxoisoindolin- 5-yl)-2- morpholino-oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 8.69 (s, 1H), 7.90 (s, 1H),7.67 (s, 1H), 4.63-4.43 (m, 3H), 4.25-4.13 (m, 1H), 3.97-3.95 (m, 4H),3.86-3.83 (m, 4H), 3.73-3.62 (m, 1H), 3.59-3.57 (m, 4H), 2.97-2.95 (m,4H), 2.42 (s, 1H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 518.1[M + H]⁺. 16 N-(2-((R)-2- fluoro-3- hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin- 5-yl)-2-((R)- 20-methyl- morpholino)oxazole-4- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.71 (s, 1H), 7.89 (s, 1H),7.67 (s, 1H), 4.63-4.43 (m, 3H), 4.24-4.04 (m, 3H), 3.97 (t, J = 4.0 Hz,4H), 3.80 (s, 2H), 3.71-3.66 (m, 3H), 3.51-3.48 (m, 1H), 2.96 (s, 4H),2.37 (s, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (s, 3H), 1.32 (s, 3H). LCMS(ESI): m/z = 532.1 [M + H]⁺.

Example 17.(R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide

a. 6-(Trifluoromethyl)picolinoyl Chloride

A solution of 6-(trifluoromethyl)picolinic acid (250 mg, 1.31 mmol) inthionyl chloride (4.75 mL, 65.4 mmol) was heated at 70° C. for 2 h. Themixture was concentrated and the crude product was used directly withoutpurification.

b.(R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide

To a solution of(R)-5-amino-2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholinoisoindolin-1-one(218 mg, 0.65 mmol) in pyridine (1.5 mL) was added the crude6-(trifluoromethyl)pyridine-2-carbonyl chloride (80 mg, 0.38 mmol). Thereaction mixture was stirred at 26° C. for 2 h and concentrated. Theresidue was taken up in ethyl acetate (30 mL), washed with water (30 mL)and brine (30 mL), dried over sodium sulfate and concentrated. Theresidue was purified by flash column chromatography (eluting with 10%ethyl acetate in petroleum ether) to give(R)—N-(2-(2-fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)-6-(trifluoromethyl)picolinamide(63 mg, 31%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 11.38; (s,1H), 8.82; (s, 1H), 8.54; (d, J=8.4 Hz, 1H), 8.20-8.16; (m, 1H), 7.94;(d, J=7.6 Hz, 1H), 7.75; (s, 1H), 4.68-4.45; (m, 3H), 4.25-4.12; (m,1H), 4.00; (t, J=4.4 Hz, 4H), 3.73-3.67; (m, 1H), 2.98; (br s, 4H),2.41; (s, 1H), 1.35; (s, 3H), 1.32; (s, 3H). LCMS (ESI): m/z=511.2;[M+H]⁺.

The following compounds were prepared using a procedure similar to thatdescribed in Example 17.

Ex. Name Structure NMR, MS 18 (R)-N-(6- (Dimethyl- amino)-2-(2-fluoro-3- hydroxy-3- methylbutyl)-1- oxoisoindolin- 5-yl)-6- (trifluoro-methyl) picolinamide

¹H NMR (400 MHz, CDCl₃) δ 11.34 (s, 1H), 8.74 (s, 1H), 8.51 (d, J = 7.6Hz, 1H), 8.16 (t, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.72 (s,1H), 4.65-4.45 (m, 3H), 4.23-4.15 (m, 1H), 3.73-3.68 (m, 1H), 2.80 (s,6H), 2.46 (s, 1H), 1.35 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 469.1[M + H]⁺. 19 N-[6-(Dimethyl- amino)-2-[(2R)- 2-fluoro-3- hydroxy-3-methyl-butyl]- 1-oxo- isoindolin- 5-yl]-6- methoxy- pyridine-2-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.32 (s, 1H), 8.74 (s, 1H), 7.91 (d, J = 7.2Hz, 1H), 7.84-7.77 (m, 1H), 7.72 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H),4.65-4.45 (m, 3H), 4.28-4.13 (m, 1H), 3.09 (s, 3H), 3.73-3.65 (m, 1H),2.78 (s, 6H), 2.47 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z= 431.1 [M + H]⁺. 20 (R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)-6-morpholino- 1-oxoiso- indolin-5- yl)thieno [2,3-b] pyrazine-7-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.79 (s, 1H), 9.04 (s, 1H), 8.89 (d, J = 2.0Hz, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 7.75 (s, 1H), 4.86-4.46 (m, 3H),4.27-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.01 (t,J = 4.4 Hz, 4H), 2.43 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI):m/z = 500.2 [M + H]⁺. 21 22 N-[2-[(2R)-2- Fluoro-3- hydroxy-3-methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5- yl]-6-[(1R)-1-hydroxy- ethyl] pyridine-2- carboxamide and N-[2-[(2R)- 2-Fluoro-3-hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5-yl]-6-[(1S)- 1-hydroxy- ethyl] pyridine-2- carboxamide (absolutestereochemistry assigned

Example 21, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 11.26 (s, 1H), 8.82 (s,1H), 8.26 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.74 (s, 1H),7.65 (d, J = 7.6 Hz, 1H), 5.13-5.10 (m, 1H), 4.67-4.46 (m, 3H), 4.24-4.15 (m, 1H), 4.06-3.94 (m, 4H), 3.71-3.65 (m, 1H), 3.29 (d, J = 4.4 Hz,1H), 2.98 (t, J = 4.4 Hz, 4H), 2.43 (s, 1H), 1.65 (d, J = 6.4 Hz, 3H),1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 487.3 [M + H]⁺. Example22, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 11.27 (s, 1H), 8.82 (s, 1H), 8.26(d, J = 8.0 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J= 7.2 Hz, 1H), 5.13-5.10 (m, 1H), 4.67-4.46 (m, 3H), 4.30- 4.13 (m, 1H),4.02-3.99 (m, 4H), 3.71-3.65 (m, 1H), 3.28 (d, J = 4.4 Hz, 1H), 2.99 (t,J = 4.8 Hz, 4H), 2.43 (s, 1H), 1.65 (d, J = 6.4 Hz, 3H), 1.35 (s, 3H),1.33 (s, 3H). LCMS (ESI): m z = 487.2 [M + H]⁺. arbitrarily) 23 24N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo-isoindolin-5- yl]-6-[(1R)-1- methoxyethyl] pyridine-2- carboxamide andN-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo-isoindolin-5- yl]-6-methoxy- ethyl]pyridine- 2-carboxamide (absolutestereochemistry assigned arbitrarily)

Example 23, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 8.83 (s,1H), 8.23 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H),7.68 (d, J = 7.6 Hz, 1H), 4.66-4.46 (m, 4H), 4.28-4.13 (m, 1H), 4.03 (t,J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.39 (s, 3H), 3.05- 2.95 (m, 4H),2.48 (s, 1H), 1.58 (d, J = 6.4 Hz, (s, 3H), 1.35, 1.33 (s, 3H). LCMS(ESI): m/z = 501.3 [M + H]⁺. Example 24, Peak 2: ¹H NMR (400 MHz, CDCl₃)δ 11.35 (s, 1H), 8.83 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.97 (t, J =7.6 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 4.66-4.46 (m, 4H),4.28-4.11 (m, 1H), 4.03 (t, J = 4.4 Hz, 4H), 3.70-3.68 (m, 1H), 3.39 (s,3H), 3.05- 2.95 (m, 4H), 2.48 (s, 1H), 1.58 (d, J = 6.4 Hz, 3H), 1.35(s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 501.3 [M + H]⁺. 25N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-isopropoxy- 1-oxo-isoindolin-5- yl]pyrazolo [1,5-a] pyrimidine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.26 (s, 1H), 8.83 (s, 1H), 8.34 (d, J = 7.2Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.4 Hz,1H), 4.66-4.50 (m, 3H), 4.46-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H),3.80-3.72 (m, 3H), 3.00 (t, J = 4.4 Hz, 4H), 2.30 (s, 1H), 1.35 (s, 3H),1.33 (s, 3H). LCMS (ESI): m/z = 525.2 [M + H]⁺. 26 N-[2-[(2R)-2-Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo- isoindolin-5-yl]-5-methyl- 4-oxo- pyrazolo [1,5-a] pyrazine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 12.22 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H),7.67 (s, 1H), 7.62 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H),4.62-4.43 (m, 3H), 4.21-4.13 (m, 1H), 3.98 (t, J = 4.4 Hz, 4H),3.74-3.63 (m, 1H), 3.68 (s, 3H), 3.00 (t, J = 4.4 Hz, 4H), 2.43 (s, 1H),1.34 (s, 3H), 1.32 (s, 3H). LCMS (ESI): m/z = 513.2 [M + H]⁺. 27N-[2-[(2R)- 2-Fluoro- 3-hydroxy- 3-methyl- butyl]-6- morpholino- 1-oxo-isoindolin-5- yl]-6-(1- hydroxy-1- methyl- ethyl) pyridine-2-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.14 (s, 1H), 8.82 (s, 1H), 8.27 (d, J = 7.6Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0 Hz,1H), 4.68-4.46 (m, 3H), 4.29-4.15 (m, 2H), 3.99 (t, J = 4.4 Hz, 4H),3.70-3.68 (m, 1H), 3.00 (t, J = 4.4 Hz, 4H), 2.46 (s, 1H), 1.69 (s, 6H),1.35 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 501.2 [M + H]⁺. 28(R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-isopropoxy- 1-oxoiso-indolin-5- yl)-7-methyl- imidazo [1,2-b] pyridazine-3- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 8.76 (s, 1H), 8.75 (s, 1H),8.42 (s, 1H), 8.23 (s, 1H), 7.37 (s, 1H), 4.98-4.88 (m, 2H), 4.57-4.37(m, 3H), 4.01-3.87 (m, 1H), 3.73- 3.69 (m, 1H), 2.51 (s, 3H), 1.46 (d, J= 5.6 Hz, 6H), 1.18 (s, 6H). LCMS (ESI): m/z = 470.2 [M + H]⁺. 29(R)-N-(2-(2- Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoiso-indolin-5- yl)-7-methyl- imidazo [1,2-b] pyridazine-3- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 8.87 (s, 1H), 8.60 (s, 1H),8.54 (d, J = 2.0 Hz, 1H), 7.96 (br s, 1H), 7.75 (s, 1H), 4.65-4.46 (m,3H), 4.28-4.14 (m, 1H), 4.00 (t, J = 4.4 Hz, 4H), 3.73-3.71 (m, 1H),3.01 (t, J = 4.0 Hz, 4H), 2.59 (s, 3H), 2.38 (s, 1H), 1.34 (s, 3H), 1.33(s, 3H). MS (ESI): m/z = 497.2 [M + H]⁺. 30 (R)-N-(2-(2- Fluoro-3-hydroxy-3- methylbutyl)- 6-(4-(oxetan- 3-yl) piperazin-1- yl)-1-oxoiso-indolin-5- yl)thieno [2,3-b] pyrazine-7- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.67 (s, 1H), 9.04 (s, 1H), 8.84 (d, J = 2.4Hz, 1H), 8.79 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 4.73-4.45 (m, 7H), 4.25-4.15 (m, 1H), 3.69-3.62 (m, 2H), 3.07 (t, J = 4.4 Hz,4H), 2.60 (br s, 4H), 2.43 (s, 1H), 1.35 (s, 3H), 1.33 (s, 3H). LCMS(ESI): m/z = 555.1 [M + H]⁺. 31 (R)-N-(2-(2- Fluoro-3- hydroxy-3-methylbutyl)- 6-(4-(oxetan- 3-yl) piperazin-1- yl)-1-oxoiso- indolin-5-yl)thieno [3,2-d) pyrimidine-7- carboxamide

¹H NMR (400 MHz, CDCl₃) δ 11.87 (s, 1H), 9.44 (s, 2H), 9.13 (s, 1H),8.78 (s, 1H), 7.77 (s, 1H), 4.73-4.45 (m, 7H), 4.25-4.15 (m, 1H),3.69-3.62 (m, 2H), 3.09 (t, J = 4.4 Hz, 4H), 2.63 (br s, 4H), 2.38 (s,1H), 1.33 (s, 3H), 1.26 (s, 3H). LCMS (ESI): mz = 555.1 [M + H]⁺. 32N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo-isoindolin-5- yl]-1H-benz- imidazole-4- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 12.55 (s, 1H), 8.83 (s, 1H),8.69 (s, 1H), 8.05 (dd, J = 7.7, 1.1 Hz, 1H), 7.84 (dd, J = 8.0, 1.1 Hz,1H), 7.55 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 4.90 (s, 1H), 4.63-4.35 (m,3H), 4.05-3.87 (m, 5H), 3.71 (td, J = 15.6, 9.3 Hz, 1H), 2.99-2.90 (m,4H), 1.23-1.15 (m, 6H). LCMS (ESI): m/z = 482.2 [M + H]⁺. 33 5-Chloro-N-[2-[(2R)-2- fluoro-3- hydroxy-3- methyl-butyl]- 6-morpholino- 1-oxo-isoindolin-5- yl]-1-methyl- pyrazole-4- carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H),7.59 (s, 1H), 4.89 (s, 1H), 4.61-4.35 (m, 3H), 4.04- 3.86 (m, 4H),3.83-3.77 (m, 4H), 3.77-3.64 (m, 1H), 2.91-2.85 (m, 4H), 1.18 (dd, J =4.3, 1.7 Hz, 6H). LCMS (ESI): m z = 480.1 [M + H]⁺. 34 (R)-N-(2-(2-Fluoro-3- hydroxy-3- methylbutyl)- 6-morpholino- 1-oxoiso- indolin-5-yl)-[1,2,4] triazolo [1,5-a] pyridine-5- carboxamide

LCMS (ESI): m z = 483.2 [M + H]⁺.

Preparation of intermediate6-(2,2,2-trifluoroethyl)pyridine-2-carboxylic Acid

a. 1-(6-Bromo-2-pyridyl)-2,2,2-trifluoro-ethanol

To a solution of 6-bromo-2-pyridinecarbaldehyde (2.0 g, 10.8 mmol) andcesium fluoride (2.4 g, 16.1 mmol) in tetrahydrofuran (10 mL) was added(trifluoromethyl)trimethylsilane (2.3 g, 16.1 mmol) at 0° C. Thereaction mixture was stirred at 25° C. for 2 h, after which it wasdiluted with water (10 mL) and extracted with dichloromethane (10 mL×3).The combined organic phase was washed with brine (10 mL×3), dried oversodium sulfate, filtered and concentrated. The residue was purified byflash chromatography (eluting gradient: 0-30% ethyl acetate in petroleumether) to afford 1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethanol (1.5 g,55%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.67; (t, J=8.0 Hz,1H), 7.58; (d, J=8.0 Hz, 1H), 7.41; (d, J=7.6 Hz, 1H), 5.03; (quintet,J=6.8 Hz, 1H), 4.78; (d, J=7.6 Hz, 1H).

b. [1-(6-Bromo-2-pyridyl)-2,2,2-trifluoro-ethyl]methanesulfonate

To a solution of 1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethanol (500 mg,1.95 mmol) and N,N-diisopropylethylamine (505 mg, 3.91 mmol) indichloromethane (2 mL) was added methanesulfonyl chloride (447 mg, 3.91mmol) at 0° C. The reaction was stirred at 0° C. for 30 min, dilutedwith water (10 mL) and extracted with dichloromethane (10 mL×3). Thecombined organic phase was washed with brine (10 mL×3), dried oversodium sulfate, filtered and concentrated. The residue was purified byflash chromatography (eluting gradient: 0-30% ethyl acetate in petroleumether) to afford [1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethyl]methanesulfonate (650 mg, 99%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 7.73-7.67; (m, 1H), 7.62-7.59; (m, 2H), 5.91; (q, J=6.0 Hz,1H), 3.17; (s, 3H).

c. Ethyl 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate

To a solution of [1-(6-bromo-2-pyridyl)-2,2,2-trifluoro-ethyl]methanesulfonate (600 mg, 1.80 mmol) in triethylamine (0.75 mL, 5.4mmol) and ethanol (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (131 mg, 0.18 mmol). The reaction was stirred at80° C. for 16 h under carbon monoxide (50 psi), filtered andconcentrated. The residue was purified by flash chromatography (elutinggradient: 0-10% ethyl acetate in petroleum ether) to afford ethyl6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate (400 mg, 96%) as a yellowoil. LCMS (ESI): m/z=234.0; [M+H]⁺.

d. 6-(2,2,2-Trifluoroethyl)pyridine-2-carboxylic Acid

To a solution of ethyl 6-(2,2,2-trifluoroethyl)pyridine-2-carboxylate(50 mg, 0.21 mmol) in water (1 mL) and ethanol (1 mL) was added lithiumhydroxide monohydrate (18 mg, 0.43 mmol). The mixture was stirred at 25°C. for 2 h. The mixture was adjusted to pH=6 with 2 M hydrochloric acidand extracted with dichloromethane (20 mL×3). The combined organic phasewas washed with brine (10 mL×3), dried over sodium sulfate, filtered andconcentrated to afford 6-(2,2,2-trifluoroethyl)pyridine e-2-carboxylicacid (40 mg, 91%) as a white solid, which was used without purification.

Preparation of Intermediate5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylic Acid a.4-Bromo-1H-pyrazole-5-carbonyl chloride

A solution of 4-bromo-1H-pyrazole-5-carboxylic acid (5.0 g, 26 mmol) inthionyl chloride (4.7 g, 39 mmol) was stirred at 100° C. for 3 h andconcentrated to obtain crude 4-bromo-1H-pyrazole-5-carbonyl chloride(5.0 g, 91%) as a yellow solid, which was used directly.

b. 4-Bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide

To a solution of aminoacetaldehyde dimethyl acetal (2.7 g, 26 mmol) indichloromethane (50 mL) was added 4-bromo-1H-pyrazole-5-carbonylchloride (5.0 g, 24 mmol). The reaction mixture was stirred at 25° C.for 3 h and concentrated. The residue was purified by flashchromatography (eluting 0-10% methanol in dichloromethane) to afford4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (6.1 g, 92%) asa white solid. ¹H NMR (400 MHz, CDCl₃): δ 11.88 (br s, 1H), 7.67; (s,1H), 7.30; (br s, 1H), 4.54; (t, J=5.2 Hz, 1H), 3.63; (t, J=5.2 Hz, 2H),3.47; (s, 6H).

c. 3-Bromo-5H-pyrazolo[1,5-a]pyrazin-4-one

To a solution of4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (3.0 g, 11mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.7 g,13 mmol). The reaction was stirred at 25° C. for 16 h and concentrated.The residue was taken up in polyphosphoric acid (10 mL) and stirred at145° C. for 5 h. Upon cooling to 0° C., the reaction mixture wasquenched with aqueous ammonium hydroxide to pH=7, diluted with water(100 mL) and extracted with dichloromethane (100 mL×3). The combinedorganic phase was washed with brine (100 mL×3), dried over sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (eluting gradient: 0-10% methanol in dichloromethane) toafford 3-bromo-5H-pyrazolo[1,5-a]pyrazin-4-one (860 mg, 37%) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD): δ 7.86; (s, 1H), 7.58; (d, J=5.6 Hz,1H), 6.81; (d, J=6.0 Hz, 1H).

d. 3-Bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one

To a solution of 3-bromo-5H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 1.87mmol) in tetrahydrofuran (5 mL) at 0° C. was added sodium hydride (90mg, 2.24 mmol) in portions and stirred at 0° C. for 30 min. Iodomethane(0.17 mL, 2.8 mmol) was added dropwise, the reaction mixture was allowedto warm to 25° C. and stirred for 2 h. The reaction was quenched withsaturated aqueous ammonium chloride (5 mL), diluted with water (10 mL)and extracted with ethyl acetate (40 mL×2). The combined organic phasewas concentrated and purified by flash chromatography (eluting gradient:0-50% ethyl acetate in petroleum ether) to afford3-bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one (350 mg, 82%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 7.77; (s, 1H), 7.40; (d, J=6.0 Hz,1H), 6.60; (d, J=6.0 Hz, 1H), 3.51; (s, 3H).

e. Ethyl 5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate

To a solution of 3-bromo-5-methyl-pyrazolo[1,5-a]pyrazin-4-one (300 mg,1.32 mmol) in ethanol (20 mL) was added triethylamine (0.18 mL, 3.95mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride(96.3 mg, 0.13 mmol). The reaction was stirred at 80° C. for 16 h undercarbon monoxide (50 psi), filtered and concentrated. The residue waspurified by flash chromatography (eluting gradient: 0-10% methanol indichloromethane) to afford ethyl5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate (80 mg, 28%) as ayellow solid. LCMS (ESI): m/z=222.0; [M+H]⁺.

f. 5-Methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylic acid

To a solution of ethyl5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylate (60 mg, 0.27 mmol)in ethanol (1 mL) and water (1 mL) was added lithium hydroxidemonohydrate (23 mg, 0.54 mmol). The reaction mixture was stirred at 25°C. for 2 h. The reaction was adjusted to pH=6 with 2 M hydrochloric acidand extracted with dichloromethane (20 mL×3). The combined organic phasewas washed with brine (10 mL×3), dried over sodium sulfate, filtered andconcentrated to afford5-methyl-4-oxo-pyrazolo[1,5-a]pyrazine-3-carboxylic acid (45.0 mg, 86%)as a white solid, which was directly used in the next step withoutpurification.

Preparation of intermediate7-methylimidazo[1,2-b]pyridazine-3-carboxylic Acid

a. (E)-N,N-Dimethyl-N′-(5-methylpyridazin-3-yl)formimidamide

A solution of 5-methylpyridazin-3-amine (2.0 g, 18 mmol) inN,N-dimethylformamide dimethyl acetal (2.7 mL, 20 mmol) was stirred at110° C. for 2 h and concentrated to affordN,N-dimethyl-N′-(5-methylpyridazin-3-yl)formamidine (3.0 g, quant.),which was used without purification.

b. Ethyl2-(dimethylamino)-7-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-3-carboxylate

To a solution of N,N-dimethyl-N′-(5-methylpyridazin-3-yl)formamidine(3.0 g, 18 mmol) in acetonitrile (20 mL) was added ethyl bromoacetate(6.1 mL, 55 mmol). The mixture was stirred at 90° C. for 12 h andconcentrated. The crude product was without purification. LCMS (ESI):m/z=251.1; [M+H]⁺.

c. Ethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate

To a solution of ethyl2-(dimethylamino)-7-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-3-carboxylate(4.9 g, 20 mmol) in acetonitrile (20 mL) was addedN,N-diisopropylethylamine (10 mL, 61 mmol). The mixture was stirred at90° C. for 12 h, concentrated and purified by chromatography on silica(eluting gradient: 0-60% ethyl acetate in petroleum ether) to affordethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate (500 mg, 12%) as ayellow solid. LCMS (ESI): m/z=205.9; [M+H]⁺.

d. 7-Methylimidazo[1,2-b]pyridazine-3-carboxylic Acid

To a solution of ethyl 7-methylimidazo[1,2-b]pyridazine-3-carboxylate(300 mg, 1.46 mmol) in tetrahydrofuran (3 mL), water (3 mL) and methanol(1.5 mL) was added lithium hydroxide hydrate (123 mg, 2.92 mmol). Thereaction mixture was stirred at 30° C. for 1 h. Hydrochloric acid (1 M)was added to adjust to pH=8-9. The solution was concentrated to affordcrude 7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid as a yellowsolid. LCMS (ESI): m/z=178; [M+H]⁺.

Preparation of Intermediate thieno[3,2-d]pyrimidine-7-carboxylic Acid

a. 7-Methylthieno[3,2-d]pyrimidine

To a suspension of 4-chloro-7-methylthieno[3,2-d]pyrimidine (500 mg,2.71 mmol), triethylamine (0.75 mL, 5.42 mmol) in ethyl acetate (7.5 mL)and 2-propanol (1.5 mL) was added 20% palladium hydroxide on carbon (250mg, 1.78 mmol). The reaction mixture was stirred at 15° C. under H₂ (15psi) for 12 h. The mixture was filtered through a pad of Celite andwashed with ethyl acetate (50 mL). The combined filtrate wasconcentrated to give 7-methylthieno[3,2-d] pyrimidine (400 mg, 98%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ 9.25; (s, 2H), 7.66; (s, 1H),2.54; (s, 3H).

b. 7-(Dibromomethyl)thieno[3,2-d]pyrimidine

A mixture of 7-methylthieno[3,2-d]pyrimidine (1.32 g, 8.79 mmol),1-bromo-2,5-pyrrolidinedione (3.9 g, 22 mmol) and benzoyl peroxide (426mg, 1.76 mmol) in carbon tetrachloride (80 mL) was stirred at 80° C. for2.5 h. The mixture was concentrated in vacuum and purified by columnchromatography (eluting gradient: 10% ethyl acetate in petroleum ether)to give 7-(dibromomethyl)thieno[3,2-d]pyrimidine (890 mg, 33%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 9.30; (s, 1H),8.48; (s, 1H), 7.21; (s, 1H).

c. Thieno[3,2-d]pyrimidine-7-carbaldehyde

A mixture of 7-(dibromomethyl)thieno[3,2-d]pyrimidine (790 mg, 2.57mmol) in water (20 mL) and pyridine (2 mL) was stirred at 100° C. for1.5 h. The mixture was cooled to 15° C. and extracted with ethyl acetate(30 mL×3). The combined organic phase was washed with brine (20 mL×2),dried over sodium sulfate, filtered and concentrated to givethieno[3,2-d]pyrimidine-7-carbaldehyde (420 mg, quant.) as a brownsolid.

d. Thieno[3,2-d]pyrimidine-7-carboxylic Acid

To a mixture of thieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.61mmol) in acetone (10 mL) and water (5 mL) was added sodium chlorite (165mg, 1.83 mmol) and sulfamic acid (89 mg, 0.91 mmol) at 0° C. undernitrogen. The mixture was heated at 40° C. for 2 h and concentrated. Theresidue was washed with water (20 mL) and ethyl acetate (20 mL) to givethieno[3,2-d]pyrimidine-7-carboxylic acid (50 mg, 46%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 13.02; (br s, 1H), 9.62; (s, 1H), 9.27; (s,1H), 9.18; (s, 1H).

Preparation of Intermediate1-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

To a solution of potassium hydroxide (1.6 g, 29 mmol) in water (3 mL)was added a solution of 2-oxo-1,2-dihydropyridine-3-carboxylic acid (2.0g, 14 mmol) in methanol (30 mL) at 10° C. After 10 min, ethyl iodide(2.5 g, 16 mmol) was added to the white mixture, and the reactionstirred at 70° C. for 20 h. The mixture was concentrated to removemethanol, and pH was to 2-3 with 1 N hydrochloric acid. The mixture wasextracted with ethyl acetate (30 mL×2). The organic layer was dried oversodium sulfate, filtered and concentrated. The residue was purified bypreparative HPLC to give 1-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid (400 mg, 2.1 mmol, 15% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 14.41; (s, 1H), 8.52; (d, J=6.8 Hz, 1H), 7.66; (m, 1H), 6.58;(m, 1H), 4.16; (q, J=7.2 Hz, 2H), 1.46; (t, J=7.2 Hz, 3H). LCMS (ESI):m/z=168.1; [M+H]⁺.

Preparation of Intermediate1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

a. Ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate

Sulfuric acid (1.2 mL, 22) was added dropwise to a solution of2-oxo-1,2-dihydropyridine-3-carboxylic acid (6 g, 43 mmol) in ethanol(200 mL) at 10° C., and the mixture was heated and stirred at 90° C. for12 h. The reaction mixture was brought to room temperature, adjusted topH=7-8 with saturated aqueous sodium bicarbonate, and extracted withethyl acetate (300 mL×5). The organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column (dichloromethane:methanol=100:1 to 10:1) to give ethyl2-oxo-1,2-dihydropyridine-3-carboxylate (3 g, 18 mmol, 42% yield) as awhite solid. LCMS (ESI): m/z=168.1; [M+H]⁺.

b. Ethyl 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate

A solution of ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1 g, 6mmol) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide(1.7 g, 15 mmol) at 10° C. 2-Iodopropane (5.4 mL, 54 mmol) was added tothe white mixture at 0° C., and the reaction mixture was stirred at 80°C. for 4 h. The mixture was adjusted to pH=2-3 with 1 N hydrochloricacid and extracted with ethyl acetate (30 mL×2). The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue waspurified by preparative HPLC to give ethyl1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 1.9 mmol,32% yield).

c. 1-Isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

To a mixture of ethyl1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 1.9 mmol)in ethanol (2 mL) was added a mixture of sodium hydroxide (153 mg, 3.82mmol) in water (500 uL) at 10° C. The reaction mixture was stirred at10° C. for 8 h, after which it was extracted with ethyl acetate (10mL×2). The aqueous layer was adjusted to pH=2˜3 with 1 N hydrochloricacid and extracted with ethyl acetate (10 mL×2). The organic layer wasdried over sodium sulfate, filtered and concentrated to give1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 51%yield) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 14.55; (s,1H), 8.49; (d, J=7.2 Hz, 1H), 7.72; (d, J=5.2 Hz, 1H), 6.63; (t, J=6.8,1H), 5.38-5.28; (m, 1H), 1.46; (d, J=6.8 Hz, 6H).

Preparation of intermediate1-Cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

a. Ethyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate

To the mixture of ethyl 2-oxo-1,2-dihydropyridine-3-carboxylate (1.2 g,7.2 mmol) in toluene (20 mL) was added cyclopropylboronic acid (1.2 g,14 mmol), copper (II) acetate (1.3 g, 7.2 mmol), followed by pyridine(2.9 mL, 36 mmol) and sodium bis(trimethylsilyl)amide (1 M, 7.2 mL)under oxygen. The mixture was stirred at 100° C. under an oxygenatmosphere (15 psi) for 24 h. The mixture was filtered and concentrated.The residue was purified by preparative HPLC to give ethyl1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 17%yield) as a white solid. LCMS (ESI): m/z=208.2; [M+H]⁺.

b. 1-Cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

To a mixture of ethyl1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.45mmol) in ethanol (2 mL) was added a mixture of sodium hydroxide (120 mg,2.9 mmol) in water (500 uL) at 12° C. The mixture was stirred at 12° C.for 8 h, after which it was extracted with ethyl acetate (10 mL×2). Theaqueous layer was adjusted to pH=2˜3 with 1 N hydrochloric acid solutionand extracted with ethyl acetate (10 mL×2). The organic layer was driedover sodium sulfate, filtered and concentrated to give1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg, 0.67mmol, 46% yield) as a light yellow solid. LCMS (ESI): m/z=180.1; [M+H]⁺.

Biological Examples

Compounds were assayed for inhibition of human IRAK4 and IRAK1 catalyticactivity using recombinant enzyme produced from insect cells.Full-length IRAK4 protein, carrying an N-terminal His6-Tag, was obtainedfrom Life Technologies (Carlsbad, Calif., USA). The IRAK1 construct wasproduced internally and was comprised of IRAK1 residues Arg194 toSer712, preceded by an NH2-terminal His6 tag and the coding sequence forglutathione-S-transferase.

Kinase activities were assayed using the Transcreener-Fluorecescencepolarization platform (BelBrook Labs, Madison, Wis., USA) that measuresamounts of the reaction product, ADP. The IRAK4 reaction conditions wereoptimized using an IRAK1-derived peptide (sequenceH-KKARFSRFAGSSPSQSSMVAR) to provide a linear reaction rate over thecourse of a 90 min incubation, which resulted in 10-12% conversion ofthe starting ATP to ADP. Final IRAK4 assay conditions were 1.25 nMIRAK4; 125 μM ATP; 10 μM MgCl2; 125 μM peptide in reaction buffer (25 mMHEPES (pH7.4); 2 mM Dithiothreitol; 0.015% Brij-35; and 0.5% dimethylsulfoxide. The IRAK1 activity was optimized similarly, yielding finalassay conditions of 1.5 nM IRAK1; 62.5 μM ATP; 5 μM MgCl2, and 62.5 μMIRAK1 peptide in reaction buffer for 60 min.

Assays of compounds for kinase inhibition were performed usinginhibitors serially-diluted in dimethyl sulfoxide, which wasaccomplished with a LabCyte Echo 555 liquid dispenser. 384 well assayplates spotted with compound received 4 μl of a 2× substrate(ATP+peptide) mix in reaction buffer, followed by 4 μl of 2× enzymediluted in reaction buffer. Reactions were halted at 60 (IRAK1) or 90(IRAK4) min by addition of 6 μl of detection buffer, containing EDTA (40nM final concentration), 0.95 μg of the ADP-binding antibody ADP2, ADPtracer (3 nM final concentration), and 25 μM HEPES. Following a 1 hrincubation, fluorescence polarization of the ADP2-antibody:TRACERcomplex was read on a Tecan M1000 plate reader using a 635/20 excitationfilter in combination with a 670/20 emission filter. Delta milli-Pvalues were analyzed using Genedata software to fit dose-response curvesand compute compound Ki values, using ATP Km values of 642 μm and 83.2μM for IRAK4 and IRAK1, respectively. Table 2 provides IRAK4 Ki valuesfor representative compounds of the present invention.

TABLE 2 IRAK4 Ki values of representative compounds of the presentinvention. IRAK4 Ki Example (uM) 1 0.0051 2 0.0032 3 0.0082 4 0.008 50.0056 6 0.0099 7 0.0064 8 0.0039 9 0.00068 10 0.0076 11 0.021 12 0.2713 0.0058 14 0.0042 15 0.0046 16 0.007 17 0.0025 18 0.0011 19 0.0015 200.0023 21 0.0017 22 0.0092 23 0.012 24 0.033 25 0.0065 26 0.047 270.0096 28 0.00082 29 0.0052 30 0.0033 31 0.005 32 0.0011 33 0.051 340.0028

The features disclosed in the foregoing description, or the followingclaims, expressed in their specific forms or in terms of a means forperforming the disclosed function, or a method or process for attainingthe disclosed result, as appropriate, may, separately, or in anycombination of such features, be utilized for realizing the invention indiverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

The patents, published applications, and scientific literature referredto herein establish the knowledge of those skilled in the art and arehereby incorporated by reference in their entirety to the same extent asif each was specifically and individually.

What is claimed is:
 1. A compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof, R¹ isC₁₋₆alkoxy, oxetanyl, —NR^(x)R^(y), or a 6-membered heteroaryl that isoptionally substituted with R^(z); R² is halogen, oxo, CN, OH,C₁₋₆alkyl, —(C₀₋₃alkyl)-C₃₋₆cycloalkyl group, a —(C₀₋₃alkyl)-3-11membered heterocyclic group, —NR^(a)R^(b), —NR^(e)C(O)R^(f),—NR^(e)S(O)₁₋₂R^(f), —C(O)(C₁₋₃alkyl), —C(O)NR^(c)R^(d), —C(O)OR^(f),—S(O)₁₋₂NR^(c)R^(d), or —(C₀₋₃alkyl)-OP(O)(OC₁₋₃alkyl)₂, wherein anyalkyl, cycloalkyl group, or heterocyclic group is independentlyoptionally substituted with halogen; oxo; CN; OR^(f); C₁₋₃haloalkoxy;—C(O)(C₁₋₃alkyl); —S—C₁₋₃alkyl; or C₁₋₃alkyl optionally substituted withOH, halogen, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, or a 3-8membered heterocyclic group, ring A is a 5-membered heteroaryl, a6-membered heteroaryl, a 6-membered saturated or partially saturatedheterocyclic group, or a 9-membered bicyclic heteroaryl that comprisesat least two heteroatoms selected form the group consisting of N, O, andS, wherein ring A is optionally substituted with R^(m); provided ring Ais not an optionally substituted 9-membered bicyclic heteroaryl of thefollowing formula,

R^(a), R^(b), R^(c) and R^(d) are, independently at each occurrence,hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11membered saturated heterocyclic group, a 5-6 membered monocyclicheteroaryl ring, —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), or—S(O)₁₋₂R^(f), or R^(c) and R^(d) are taken together to form a 5-8membered heterocyclic group, wherein any alkyl, cycloalkyl group,phenyl, heterocyclic group, or heteroaryl ring is independentlyoptionally substituted with halogen, oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl,C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(f), —NR^(g)R^(h), or a 5-6 memberedmonocyclic heteroaryl ring; R^(e) is, independently at each occurrence,hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl group, wherein any alkyl orcycloalkyl group is independently optionally substituted with halogen,oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;R^(f) is, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl group, or a 3-11 membered saturated heterocyclic group,wherein any alkyl, cycloalkyl group, or heterocyclic group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, —OR^(e), or—NR^(g)R^(h); R^(g) and R^(h) are, independently at each occurrence,hydrogen, C₁₋₃alkyl, or C₃₋₆cycloalkyl group, wherein any alkyl orcycloalkyl group is independently optionally substituted with halogen,oxo, CN, OH, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy;each R^(m) is, independently at each occurrence, halogen; oxo; CN;—OR^(v); —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy; —NR^(n)R^(p); —C(O)(C₁₋₃alkyl);—(C₀₋₃alkyl)C(O)NR^(r)R^(s); —S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂;C₃₋₁₀cycloalkyl group optionally substituted with OH or halogen; a 3-11membered saturated or partially saturated heterocyclic group optionallysubstituted with oxo or C₁₋₃alkyl; a 5-6 membered monocyclic heteroarylring optionally substituted with halogen, oxo, CN, OH, C₁₋₄alkoxy,—NR^(n)R^(p), or C₁₋₄alkyl optionally substituted with halogen, or OH;or C₁₋₄alkyl optionally substituted with halogen, oxo, CN, OH,—O—C₁₋₃alkyl, —S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p),—C(O)NR^(n)R^(p), phenyl, C₃₋₁₀cycloalkyl, a 3-11 membered saturated orpartially saturated heterocyclic group optionally substituted with oxo,C₁₋₃ alkyl, or a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with oxo, halogen, or C₁₋₃alkyl; R^(n), R^(p), R^(r) andR^(s) are, independently at each occurrence, hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl group, —(C₀₋₃alkyl)-phenyl, a 3-11 membered saturatedheterocyclic group, a 5-6 membered monocyclic heteroaryl ring,—C(O)R^(v), —C(O)OR^(v), —C(O)NR^(t)R^(u), or —S(O)₁₋₂R^(v), or R^(r)and R^(s) are taken together to form a 5-8 membered heterocyclic group,wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, orheteroaryl ring is independently optionally substituted with halogen,oxo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(v),—NR^(t)R^(u), or a 5-6 membered monocyclic heteroaryl ring; R^(t) andR^(u) are, independently at each occurrence, hydrogen, C₁₋₃alkyl, orC₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; R^(v) is,independently at each occurrence, hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkylgroup, or a 3-11 membered saturated heterocyclic group, wherein anyalkyl, cycloalkyl group, or heterocyclic group is independentlyoptionally substituted with halogen, oxo, CN, OH, C₁₋₃alkyl,C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, —OR^(w), or —NR^(t)R^(u); andR^(w) is, independently at each occurrence, hydrogen, C₁₋₆alkyl orC₃₋₆cycloalkyl group, wherein any alkyl or cycloalkyl group isindependently optionally substituted with halogen, oxo, CN, OH,C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy, or C₁₋₃haloalkoxy; R^(x) and R^(y)are, independently at each occurrence, C₁₋₆alkyl, or R^(x) and R^(y) aretaken together to form a 6-membered heterocyclic group that isoptionally substituted with R^(z); each R^(z) is, independently at eachoccurrence, halogen; oxo; CN; —S(O)₁₋₂R^(v); OH; C₁₋₆alkoxy;—NR^(n)R^(p); —C(O)(C₁₋₃alkyl); —(C₀₋₃alkyl)C(O)NR^(n)R^(p);—S(O)₁₋₂NR^(n)R^(p); —OP(O)(OC₁₋₃alkyl)₂; C₃₋₁₀cycloalkyl groupoptionally substituted with OH or halogen; a 3-11 membered saturated orpartially saturated heterocyclic group optionally substituted with oxoor C₁₋₃alkyl; a 5-6 membered monocyclic heteroaryl ring optionallysubstituted with halogen, oxo, CN, OH, C₁₋₄alkoxy, —NR^(n)R^(p), orC₁₋₄alkyl optionally substituted with halogen, or OH; or C₁₋₄alkyloptionally substituted with halogen, oxo, CN, OH, —O—C₁₋₃ alkyl,—S—C₁₋₃alkyl, —SO₂—C₁₋₃alkyl, —NR^(n)R^(p), —C(O)NR^(n)R^(p), phenyl,C₃₋₁₀cycloalkyl, a 3-11 membered saturated or partially saturatedheterocyclic group optionally substituted with oxo, C₁₋₃ alkyl, or a 5-6membered monocyclic heteroaryl ring optionally substituted with oxo,halogen, or C₁₋₃alkyl.
 2. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, wherein R¹ is —NR^(x)R^(y). 3.The compound of claim 2, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R^(x) and R^(y) are taken together toform a 6-membered heterocyclic group that is optionally substituted withR^(z).
 4. The compound of claim 2, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R^(x) and R^(y) are taken together toform a morpholino group that is optionally substituted with R^(z). 5.The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R¹ is a 6-membered heteroaryl that isoptionally substituted with R^(z).
 6. The compound or salt of claim 5wherein R¹ is pyridyl that is optionally substituted with R^(z).
 7. Thecompound of claim 1, or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein R¹ is selected from the group consisting of


8. The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R² is


9. The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R² is


10. The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein ring A is selected from the groupconsisting of


11. The compound of claim 10, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein ring A is selected from the groupconsisting of


12. The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R^(m) is selected from the groupconsisting of chloro, oxo, methyl, ethyl, isopropyl, cyclopropyl,trifluoromethyl, CN, methoxy, OH, isopropoxy, 2,2,2-trifluoroethyl,1-hydroxyethyl, 1-methoxyethyl, 2-hydroxyprop-2-yl, morpholino,20methylmorpholino, and 1H-pyrrol-3-yloxy.
 13. The compound of claim 1,selected from the group consisting of

or a stereoisomer or pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition comprising a compound of a claim 1, or astereoisomer or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient, carrier or diluent.